Bronchial asthma is a chronic disease characterized by bronchial hyperresponsiveness and intermittent airway constriction due to chronic airway inflammation, thereby causing symptoms of respiratory distress, and it is known that there is no complete cure for bronchial asthma. Bronchial asthma is a very common disease that occurs in about 5 to 10% of the total population in the majority of countries around the world, including the Republic of Korea. Recently, the prevalence of bronchial asthma has increased globally with environmental changes.
Asthma is an allergic disorder, characterized by chronic airway inflammation and bronchial hyperresponsiveness. However, it has been recently reported that asthma is associated with various pathophysiological conditions as well as irreversible pathological changes of airway tissue. In this case, persistent inflammation leads to acute and chronic airway and lung damage and consequently to common pathophysiological processes characterized by inflammation and fibrosis, and these various pathological changes are collectively referred to as airway remodeling in asthma. At present, there are no effective medications for these changes, resulting in a pathological cause of severe asthma. For typical asthma, from a pathophysiological point of view, asthma is recognized as an inflammatory disease caused by proliferation, differentiation and activation of inflammatory cells by cytokines produced by T-helper type 2 (Th2) cells, followed by migration and infiltration into the airway and surrounding tissues. In this case, it is known that inflammatory cells, such as activated eosinophils, mast cells, alveolar macrophages, etc., secrete various inflammatory mediators to induce bronchoconstriction and eosinophilia, and an increase in inflammatory mediators produced by eosinophils is an important factor in aggravating asthma. Therefore, asthma medications that have been developed and used are mainly aimed at suppressing the production of Th2 cytokines such as interleukin-4, interleukin-5, interleukin-13, etc. which are involved in production and activation of inflammatory cells in lung tissues, thereby inducing inhibition of airway inflammation (lymphocytes, eosinophils, neutrophils).
Inhaled steroids, which are used as one of the most effective medications, are effective for typical asthma, but not for steroid-resistant asthma or severe asthma that accounts for 5-15% of all patients. These patients have little response to the medications used and thus are hard to treat, unlike other patients. Patients with asthma that is not satisfactorily controlled despite the use of various medications including these inhaled steroids are defined as severe asthma, refractory asthma, or difficult to treat asthma, and characterized by persistent symptoms, frequent acute exacerbations, frequent use of systemic steroids, and frequent use of short-acting bronchodilators. Despite the development of various medications, the increase in prevalence of asthma and related mortality is due to the fact that there is no fundamental treatment for refractory severe asthma that is a common etiology. Therefore, recent trends in the development of asthma medications are focused on the development of drugs with mechanisms to overcome these severe asthma conditions.
Adults with this severe asthma are more likely to have neutrophilic airway inflammation than those with typical asthma, are highly likely to experience acute exacerbation, and exhibit severe inflammation unresponsive to steroids and bronchial hyperresponsiveness. Moreover, the importance of innate immunity in the occurrence of neutrophilic severe asthma has been emphasized, unlike the previous concept of the pathophysiology of allergic asthma.
Meanwhile, an RNA-dependent protein kinase (PKR) is specifically a serine/threonine kinase, which plays an important role in innate immune response that is activated upon viral infection in vivo. It has been recently reported that PKR plays its role in intracellular signalling pathways of Toll-like receptors, which are receptor systems recognizing external infectious agents, affecting immune responses in the lung; however, its therapeutic effects on diseases using biological models have not yet been evaluated.
As described above, it has not yet been investigated whether the PKR inhibitor has a therapeutic effect on severe asthma, and there have been no studies on this. Therefore, the inventors of the present invention have conducted research using the PKR inhibitor to develop a new drug having a therapeutic effect on severe asthma, and found that the PKR inhibitor has an excellent effect of treating severe asthma, thereby completing the present invention.